Despite recent advances, more effective agents are critically needed for patients with metastatic melanoma. One exciting approach is immunotherapy, which utilizes the patient's immune system to destroy cancer cells. Drugs such as anti-CTLA-4 (ipilimumab) release the brakes on specialized white blood cells (T cells) to boost anti-tumor immunity. Unfortunately, monotherapy typically benefits only a subset of patients, which may be due to tumor-induced suppression of the immune response. One way tumors suppress the immune system is by secreting an inhibitory protein, called galectin-3 (Gal-3). Gal-3 enhances tumor growth and metastasis and can also suppress the function of tumor-specific T cells. Given the ability of CTLA-4 and Gal-3 to suppress anti- tumor immunity, the central hypothesis of this proposal is that treatment with a novel Gal-3 inhibitor (GR-MD- 02) plus CTLA-4 blockade (ipilimumab) will enhance tumor regression in patients with advanced melanoma by boosting the function of tumor-specific T cells. This is an innovative approach that targets two unique regulatory pathways to change the tumor microenvironment and enhance T cell activity. Importantly, pre- clinical studies revealed that combined GR-MD-02/anti-CTLA-4 therapy significantly boosted tumor regression and increased the survival of tumor-bearing mice. These data provide a strong rationale for testing the clinical and immunological activity of ipilimumab plus GR-MD-02 in patients with metastatic melanoma. The proposed research is significant because if the immune enhancing and anti-tumor effects from the pre-clinical models are also observed in humans, then clinical care will be considerably enhanced. The objective of this application is to investigate the safety and efficacy of combined GR-MD-02/ipilimumab therapy in a phase I clinical trial and identify the mechanisms by which these agents augment tumor-specific immunity. The goals are to: 1) Determine the safety and efficacy of this novel combination for patients with metastatic melanoma; and 2) Elucidate the mechanisms by which combined GR-MD-02/ipilimumab therapy boosts anti-tumor immunity.